Use of antiretroviral therapy can lead to immune reconstitution hepatitis in HIV/HBV-coinfected patients even if they are taking lamivudine, according to a pair of case reports in the July 1st edition of Clinical Infectious Diseases.
Hepatitis B coinfection is present in an estimated 5-10% of HIV positive individuals. HBV-related liver damage is primarily due not to the action of the virus itself, but rather to the immune system’s response. In particular, CD8 lymphocytes target HBV-infected hepatocytes, leading to inflammation and cell death. HIV/HBV coinfection can cause more rapid HBV disease progression, although most studies show it does not worsen the course of HIV disease.
Acute hepatitis flare-ups are known to occur when HBV replication increases, as may happen when drugs active against HBV are discontinued. In coinfected individuals, this is often seen when patients stop taking lamivudine (3TC or Epivir), a nucleoside reverse transcriptase inhibitor active against both HBV and HIV, or when HBV develops resistance to the drug. Such flares may also occur when effective HAART produces immune reconstitution, enabling immune cells to step up their inflammatory response. Symptoms of acute hepatitis – including increased liver enzyme levels, fatigue, loss of appetite, and jaundice -- may also be due to liver toxicity related to anti-HIV medications.
Anne Drake from the Royal Melbourne Hospital in Melbourne and colleagues described two HIV/HBV-coinfected patients who experienced liver disease flare-ups after starting HAART that included lamivudine.
The first patient was a 38-year-old Ethiopian woman with a CD4 cell count of 203 cells/mm3 and an HIV viral load of 94,800 copies/mL. The woman had asymptomatic chronic HBV infection with normal liver enzyme levels. After a three-month treatment interruption, she resumed therapy with lamivudine, stavudine (d4T or Zerit), indinavir (Crixivan), and low-dose ritonavir (Norvir), a regimen she had previously taken for eight months with no complications. Two weeks after restarting HAART, she developed fatigue, abdominal pain, jaundice, and abnormal liver function tests, including elevated ALT, AST, and bilirubin. By this time, her CD4 count had nearly doubled (to 452 cells/mL), indicating immune reconstitution.
Treatment with stavudine, indinavir, and ritonavir were stopped, but she continued to receive lamivudine. After a week, her symptoms stabilized and her liver enzyme levels decreased, but her jaundice worsened and her liver synthetic function (ability to produce proteins) deteriorated. She then started tenofovir (Viread), another drug active against both HBV and HIV, whereupon her symptoms resolved and her HBV viral load became undetectable; AZT (zidovudine or Retrovir) and abacavir (Ziagen) were later added to her regimen. Laboratory tests showed no evidence of lamivudine-resistant HBV, and a liver biopsy revealed stage 3 fibrosis and grade 2 necroinflammatory activity.
The second patient was a 45-year-old woman from Ghana admitted with septic shock and multiorgan failure due to Salmonella infection. Her liver function tests were abnormal and she had liver and spleen enlargement. She also had a positive PCR test for hepatitis D (HDV), a virus that can occur with HBV resulting in more severe liver disease. The woman slowly recovered with antibiotic treatment; she was also treated for cytomegalovirus infection and toxoplasmosis.
After two months, her health (including her liver function tests) had improved enough to begin HAART with lamivudine, abacavir, indinavir, and low-dose ritonavir. Four weeks later, she developed vomiting, abdominal pain, and deteriorating liver function. A liver biopsy revealed stage 4 fibrosis and grade 3 necroinflammatory activity.
The woman’s CD4 count rose from 62 cells/mm3 at the start of treatment to 96 cells/mm3, indicating that while she was still severely immunocompromised, she experienced some immune reconstitution. Her HIV viral load became undetectable (less than 50 copies/mL), and her HBV viral load decreased; laboratory tests showed no evidence of lamivudine-resistant HBV.
Unfortunately, her health continued to deteriorate and her liver function worsened. Despite administration of high-dose steroids to control inflammation, she developed progressive liver and kidney failure and died after 122 days of hospitalization.
Given that both HIV/HBV-coinfected patients developed clinical liver disease flares within weeks after starting (or restarting) HAART and achieving CD4 cell increases – and in the absence of alternative explanations – the authors concluded that immune reconstitution was the likely cause of the women’s acute hepatitis. In both cases, hepatitis flare-ups occurred despite the use of lamivudine. Neither woman received nevirapine (Viramune) or full-dose ritonavir, the anti-HIV drugs most often associated with severe hepatotoxicity.
In order to prevent such flares, HBV replication should be controlled before or concurrently with the initiation of HAART. In both these cases, hepatitis flares occurred despite the inclusion of lamivudine in patients who showed no evidence of lamivudine-resistant HBV. However, immune reconstitution can occur within days of starting HAART, before lamivudine has had time to control HBV replication (which can take as long as a month). Therefore, the authors emphasised the need to “maximally suppress HBV replication from the outset.”
The patient who recovered did so following the addition of tenofovir, and studies have shown that lamivudine plus tenofovir reduces HBV viral load more effectively than lamivudine alone.
The authors recommend that combination therapy with lamivudine plus tenofovir “should be employed at least for cirrhotic patients at risk for hepatic decompensation and, perhaps, even for all coinfected patients with HBV replication.”
They also suggest that the addition of other anti-HIV drugs might be delayed in order to slow the rate of immune reconstitution and allow time for lamivudine and tenofovir to suppress HBV replication. Finally, they recommend that HBV viral load and the extent of liver damage should be assessed before starting HAART in HIV/HBV-coinfected individuals, since those with advanced fibrosis or cirrhosis are more likely to suffer liver failure as a consequence of immune reconstitution hepatitis flares.
Reference
Drake A et al. Immune reconstitution hepatitis in HIV and hepatitis B coinfection, despite lamivudine therapy as part of HAART. Clin Infect Dis 39, 2004.